PMID- 32964723 OWN - NLM STAT- MEDLINE DCOM- 20210107 LR - 20211203 IS - 1522-1504 (Electronic) IS - 1040-0605 (Print) IS - 1040-0605 (Linking) VI - 319 IP - 6 DP - 2020 Dec 1 TI - Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease. PG - L1021-L1035 LID - 10.1152/ajplung.00207.2020 [doi] AB - S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9(-/-) mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicle-administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD. FAU - Railwah, Christopher AU - Railwah C AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Lora, Alnardo AU - Lora A AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Zahid, Kanza AU - Zahid K AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Goldenberg, Hannah AU - Goldenberg H AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Campos, Michael AU - Campos M AD - Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami Miller School of Medicine, Miami, Florida. FAU - Wyman, Anne AU - Wyman A AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Jundi, Bakr AU - Jundi B AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Ploszaj, Magdalena AU - Ploszaj M AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Rivas, Melissa AU - Rivas M AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Dabo, Abdoulaye AU - Dabo A AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. AD - Department of Cell Biology, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - Majka, Susan M AU - Majka SM AD - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado. FAU - Foronjy, Robert AU - Foronjy R AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. AD - Department of Cell Biology, State University of New York Downstate Health Sciences University, Brooklyn, New York. FAU - El Gazzar, Mohamed AU - El Gazzar M AD - Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. FAU - Geraghty, Patrick AU - Geraghty P AUID- ORCID: 0000-0003-1647-5505 AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York. AD - Department of Cell Biology, State University of New York Downstate Health Sciences University, Brooklyn, New York. LA - eng GR - R01 HL116597/HL/NHLBI NIH HHS/United States GR - R01 HL136449/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200923 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Calgranulin B) RN - 0 (Inflammation Mediators) RN - 0 (Receptor for Advanced Glycation End Products) RN - 0 (S100A9 protein, mouse) RN - 0 (Smoke) SB - IM MH - Animals MH - Calgranulin B/*metabolism MH - Inflammation Mediators/*metabolism MH - Lung/metabolism MH - Mice MH - Pulmonary Disease, Chronic Obstructive/chemically induced/*etiology/metabolism MH - Pulmonary Emphysema/metabolism MH - Receptor for Advanced Glycation End Products/metabolism MH - Smoke/*adverse effects MH - Vital Capacity/physiology PMC - PMC7938777 OTO - NOTNLM OT - S100A9 OT - aging OT - cigarette smoke OT - kinase OT - pulmonary function EDAT- 2020/09/24 06:00 MHDA- 2021/01/08 06:00 PMCR- 2021/12/01 CRDT- 2020/09/23 08:38 PHST- 2020/09/24 06:00 [pubmed] PHST- 2021/01/08 06:00 [medline] PHST- 2020/09/23 08:38 [entrez] PHST- 2021/12/01 00:00 [pmc-release] AID - L-00207-2020 [pii] AID - 10.1152/ajplung.00207.2020 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2020 Dec 1;319(6):L1021-L1035. doi: 10.1152/ajplung.00207.2020. Epub 2020 Sep 23.